Quinapril is the common international denomination of the chemical compound named (S)-2-[(S)—N—[(S)-1-(ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid]. Quinapril and its pharmaceutically acceptable salts are antihypertensive agents which act as angiotensin converting enzyme (ACE) inhibitors.
The first description of quinapril appears in the U.S. Pat. No. 4,344,949, which also describes its preparation starting from the ethyl ester of (S,S)-α-[(1-carboxyethyl)amino] phenylbutanoic acid and from the benzyl or t-butyl ester of (S)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid by peptide condensation with dicyclohexyl-carboimide (DCC) and activation with hydroxibenzotriazole. The benzyl or t-butyl ester of quinapril so obtained is unprotected by catalytic hydrogenation or by treatment with trifluoroacetic acid, being the final isolation of quinapril carried out (at the laboratory scale by preception with ethyl either and by lyophilization of an aqueous solution. The isolation of quinapril is a very delicate procedure, as this product degrades very easily by intramolecular cyclisation to yield a diketopiperazine of formula both in aqueous or organic solution as in the solid state.
The process described in said patent U.S. Pat. No. 4,344,949 presents the drawbacks which are typical of the use of DCC, as the condensations carried out in the presence of DCC yield a fair amount of impurities, with the subsequent reduction in the yield (61%), thus the resulting dicylohexylurea must be separated and, additionally, the carbodiimides are responsible for very severe allergies.
Quinapril hydrochloride is the salt which is usually employed in the manufacture medicinal products which contain quinapril.
The U.S. Pat. No. 4,761,479 mentions that obtaining and purifying quinapril hydrochloride is hindered by its ease in degrading into by-products, essentially the diketopiperazine shown before. Said U.S. Pat. No. 4,761,479 describes a process for obtaining quinapril hydrochloride which comprises unprotecting the t-butyl ester of quinapril with HCl gas in acetic acid, the isolation of the precipitation product after the addition of xylene and vacuum distillation, and the purification of the quinapril hydrochloride by crystallisation with acetonitrile to yield a crystalline solvate of acetonitrile. The solvent of said solvate can be removed, without degradation of the quinapril hydrochloride, by drying in a vacuum oven. However, acetonitrile is a Class 2 solvent, defined by the ICH [International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use] as a “Non-mutagenic carcinogen in animals or possible cause of other irreversible toxicity such as neurotoxicity, teratogenesis or suspect of significant reversible toxicity, and, therefore, its proportion has to be limited”. In the case of acetonitrile, the ICH recommends a limit not above 250 ppm (0.025%). This limit is difficult to achieve at the industrial scale due to the little stability of the product.
The Belgian Patent No. BE 892.552 describes another process for the preparation of quinapril hydrochloride starting from (S,S)-α-[(1-carboxyethyl)amino]phenylbutanoic acid by activation with 1,1′-carbonyldiimidazole, which yields an N-carboxyanhydride which reacts in situ, without prior isolation, with the benzyl ester of (S)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid to yield the corresponding benzyl ester of quinapril with a yield of 56%. The resulting quinapril, protected in the form of a benzyl ester, is subsequently hydrogenated in the presence of Pd/C and it is treated with hydrochloric acid to give the quinapril hydrochloride, which is purified by chromatography and lyophilization, at a very low yield (37%). This synthetic route is also mentioned in a generic manner in the Spanish Patent ES 2.004.804, but without giving any specific conditions, nor yields, nor a description of the properties of the products obtained. Specifically, the synthesis of quinapril hydrochloride is not exemplified at all.
In general, all the processes described for obtaining quinapril hydrochloride are characterised by their difficulty or by their low yields. Only the U.S. Pat. No. 4,761,479 describes a process for the industrial isolation and purification of quinapril hydrochloride, starting from the t-butyl ester of quinapril. However, said procedure has the disadvantage of using a carcinogenic solvent (acetonitrile) to obtain the corresponding solvate.
Consequently, there is a need to have a process for obtaining and purifying quinapril hydrochloride, which may be carried out at the industrial scale, and which overcomes the previously mentioned drawbacks. In order to obtain and purify quinapril hydrochloride at a high yield, the invention proposes the precipitation of said product in the form of a toluene solvate. Therefore, one of the objects of the inventon is constituted by a process for obtaining quinapril hydrochloride, which comprises its isolation as the toluene solvate.
On the other hand, the solvates of quinapril hydrochloride, which are useful compounds for the purification of said product, are, in general, products from which it is extremely difficult to remove the solvent without partially degrading the quinapril hydrochloride. The only known solvate of quinapril hydrochloride which can be dried without degradation of the product is the acetonitrile solvate, but said solvate has been obtained with a carcinogenic solvent. In order to overcome these drawbacks, the invention provides solvates of quinapril hydrochloride which can be dried to remove the solvent without degrading the quinapril hydrochloride, and which have been obtained by the use of non-carcinogenic solvents. Therefore, an additional object of the invention is constituted by new solvates of quinapril hydrochloride, of solvents belonging to Class 3, from which it is possible to remove the solvent by drying without degradation of quinapril hydrochloride. Class 3 solvents are defined, according to the ICH, as “Solvents with a low toxic potential to man, not being it necessary to establish an exposure limit based on health criteria. Class 3 solvents have a ADE (Allowable Daily Exposure) equal or greater than 50 mg per day”.